| Trypanosoma brucei is the protozoan causative agent of the sleeping sickness or Human African Trypanosomiasis. This infectious vector-borne disease occurs in sub-Saharan African countries and is transmitted through the bite of a specific vector, the tsetse fly. Each year, HAT accounts for 10 000 new infections and a mortality rate of approximately 6000 patients. The current chemotherapy is unsatisfactory as it consists of only four drugs in complex dosing or admission programs, requiring specifically trained staff. In addition, these drugs have severe toxic side effects and the occurrence of drug-resistant trypanosome strains is a growing problem. For those reasons, there is an urgent need to discover and develop new drugs for the treatment of HAT. Metacaspases (MCAs) represent a new family of important proteases found in almost all eukaryotic organisms, but not in metazoa. In T. brucei, five metacaspases have been identified which are considered a valuable new drug target in drug research and development for several reasons. They are possibly involved in programmed cell death, considered vital for the survival of the parasite and are significantly different from the orthologous human caspases.;During this PhD fellowship, optimization efforts of the lead compound UAMC-00599 at the P1 and P2 position resulted in several TbMCA2 inhibitors with higher enzymatic inhibitory activities. Unfortunately, none of the synthesized compounds displayed substantial antiparasitic activity. Furthermore, the first probes towards the MCAs of T. brucei were designed and synthesized. Biotinylated compounds were obtained, but did not contain the vinylic function due to intramolecular cyclization following the Homer-Wadsworth-Emmons olefination. However, a Lys P1 containing a functional vinyl sulfone inhibitor was synthesized but did not show activity towards the enzyme. Finally, we described the previously unreported intramolecular ring formation observed during the synthesis and biochemical evaluation of TbMCA inhibitors with an Arg residue at the P1 position and a phenyl vinyl sulfone warhead. To avoid this unwanted reaction, other Michael acceptor warheads were introduced, which resulted in the first 'stable' (no ring formation) Michael acceptor-containing TbMCA2 inhibitors. However, these compounds did not show inhibitory activity towards the enzyme or the parasite. |
